09 August 2022
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Original Citation:
Integrin signalling adaptors: not only figurants in the cancer story
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DOI:10.1038/nrc2967
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1
This is an author version of the contribution published on:
Nat Rev Cancer. 2010 Dec;10(12):858-70. doi: 10.1038/nrc2967.
Questa è la versione dell’autore dell’opera:
ovvero
Integrin signalling adaptors: not only figurants in the cancer story.
Cabodi S
1
, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P.
The definitive version is available at:
La versione definitiva è disponibile alla URL:
http://www.nature.com/nrc/journal/v10/n12/full/nrc2967.html
2
Integrin signalling adaptors: not only figurants in the cancer story
Authors:
Sara Cabodi, Maria del Pilar Camacho-Leal, Paola Di Stefano and Paola Defilippi
Molecular Biotechnology Centre and Dept. of Genetics, Biology and Biochemistry, University of
Torino
Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126, Torino (I) e-mail:
paola.defilippi@unito.it
Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling
platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor
receptor activation. The understanding of the biological effects regulated by these adaptors in
tumours might be crucial for the identification of novel targets and the development of innovative
therapeutic strategies for human cancer. In this review we will discuss the relevance of adaptor
proteins in signalling originating from integrin-mediated cell-extracellular matrix (ECM) adhesion
and growth factor stimulation within the context of cell transformation and tumour progression.
Herein, we will specifically underline the contribution of p130CAS, NEDD9, CRK, and the IPP
complex (ILK, PINCH and PARVIN) to cancer, along with the more recently identified p140CAP.
Introduction
In the last fifteen years integrin signalling has been profoundly implicated in cancer cell
proliferation, survival and invasion
1
. Current knowledge implies that in cancer cells integrins,
receptor tyrosine kinases (RTKs) and cytokine receptors constitute joint modules in which
attachment to the ECM confers positional control to the activated signalling pathways allowing
cells to respond to soluble growth factors, which thereby determine the nature and the extent of the
response
1,2
. This control mainly resides on the recruitment of adaptor proteins that behave as
molecular hubs for intracellular signalling and organise complex signalling networks in time and
space
3-6
. The biological effects regulated by integrin and RTK signalling adaptors are dependent on
their expression levels and on their phosphorylation status, which determines the association with
binding effectors.
The integrin signalling adaptors represent crucial players in cell transformation and
invasion, mostly by regulating basic processes such as cell cycle control, survival, cytoskeletal re-
organisation and migration. Recent studies highlight the relevance of specific families of these
scaffold molecules in many human cancers and show that interfering with their expression and/or
3
with their ability to bind effector proteins is therapeutically efficacious to inhibit tumorigenesis
sustained by integrin and growth factor receptor co-operation. This Review will discuss how the
expression of integrin adaptors is related to human cancer, their relevance in animal models of
tumorigenesis and their role in cancer cell biology.
Integrin adaptors in cancer
In the following paragraphs we will review recent data that highlight how the altered expression of
the integrin adaptors is related to tumorigenesis. p130CAS, NEDD9, CRK, the IPP complex (ILK,
PINCH and PARVIN) and p140CAP adaptors are crucial effectors of integrin and RTKs signalling,
acting as multi-site scaffolds that integrate and propagate signals from ECM and soluble ligands to
intracellular signalling pathways, promoting cell proliferation, survival and motility.
The CAS family. The CAS family comprises four members: p130CAS (also known as breast cancer
anti-oestrogen resistance 1 (BCAR1)), NEDD9 (also known as HEF1 or CAS-L), embryonal Fyn-
associated substrate (EFS, also known as SIN) and CAS scaffolding protein family member 4
(CASS4, also known as HEPL). They are characterized by the presence of multiple conserved
sequence motifs, such as SH3 and proline-rich domains and extensive post-translational
modifications, mainly consisting of tyrosine and serine phosphorylation
3,4
(Figure 1). CAS proteins
differ in patterns of expression, for esample in normal tissues, whilst p130CAS is ubiquitously
expressed, NEDD9 expression is confined to the lungs and kidneys
3,4
. CASS4
7
and EFS
8
are less
abundant and specifically expressed in spleen and lung (CASS4) and T- lymphocytes, thymus, brain
and skeletal tissue (EFS), making their functions limited to specific context.
Overexpression of CAS proteins contributes to the development of human cancer. p130CAS
is necessary for transformation by several oncogenes, such as SRC, ERBB2 (also known as HER2)
and nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion protein
9-11
. Recently,
p130CAS has been shown to be required for KRAS, BRAF, PTEN and PIK3CA oncogene-dependent
proliferation
12
. Nevertheless, investigation of its expression in biopsies of different human
malignancies using immunohistochemistry is still limited to breast cancer and haematological
malignancies (Table I). Recently it has been reported that in human breast cancers overexpression
of both ERBB2 and p130CAS is associated with increased proliferation, metastasis formation and
poor prognosis
13,14
(Table I). Consistently, double transgenic mice overexpressing both p130CAS
and ERBB2 in the mammary gland show an accelerated onset of tumour formation, providing
evidence that p130CAS and the ERBB2 oncogene synergise in vivo to transform the mammary
epithelium
13
(Table II). Indeed p130CAS silencing in ERBB2 transformed breast cancer cells is
4
sufficient to inhibit tumour growth in vivo, and correlates with downregulation of proliferative and
survival pathways, such as SRC and AKT activation, focal adhesion kinase (FAK) phosphorylation
and CYCLIN D1 expression
11
. In oestrogen receptor (ER)-positive human breast tumours,
overexpression of p130CAS correlates with intrinsic resistance to tamoxifen treatment in a large
subset of human breast cancer samples
15-17
.
The second member of the family, NEDD9, has been identified as a metastasis gene in
melanoma and in head and neck squamous cell carcinoma (HNSCC). Indeed its expression levels is
elevated in human metastatic melanoma compared with primary melanoma
18,19
and in invasive
HNSCC
20
. Recently, a role in mammary tumorigenesis has also been proposed for NEDD9, whose
absence significantly impairs tumour formation induced by the polyoma virus middle T oncogene
(PyMT)
21
(Table II).
Overall, p130CAS and NEDD9 expression levels are critical for onset and progression of
many aggressive cancers, highlighting their importance as new unfavourable prognostic markers.
The CRK family. The CRK family consists of three members: CRK-I, CRK-II
22
, alternative
transcripts of the same gene, and CRKL
23
(Figure 1). The CRK family SH2 domains can bind to a
variety of key signalling molecules including p130CAS.
The CRK family has been shown to be overexpressed in lung adenocarcinoma
24
, human
colon cancers
25
and malignant glioblastoma
26,27
. High levels of CRK mRNA and protein expression
correlate with increased tumour aggressiveness in lung, contributing to poor prognosis and shorter
survival
24
. Recently, it was shown that CRK is a key regulator of mammary gland tumorigenesis. A
subset of mouse mammary tumour virus (MMTV)-CRK transgenic mice develop focal mammary
tumours with a latency of 15 months, suggesting a potential role of CRK in integrating signals for
breast cancer progression in vivo
28
(Table II).
The IPP complex. The IPP adaptor complex comprises the integrin-linked kinase (ILK), PINCH1
(also known as LIM and senescent cell antigen-like domains 1 (LIMS1)) and PINCH2 (also known
as LIMS2) and PARVIN and (Figure 1).
The expression of ILK has been analysed in a large number of human malignancies
29-31
and
is often found to be elevated and associated with tumour progression and shortened survival (Table
1). Increased ILK expression has been associated with more differentiated areas of malignant
gastrointestinal, renal, neural and bone marrow tumours, suggesting that ILK might be also an
indicator of differentiation
29,32
.
